Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland.
Biol Psychiatry. 2020 Dec 15;88(12):935-944. doi: 10.1016/j.biopsych.2020.02.014. Epub 2020 Feb 24.
Maintenance treatment with opioid agonists (buprenorphine, methadone) is effective for opioid addiction but does not eliminate opioid use in all patients. We modeled maintenance treatment in rats that self-administered the prescription opioid oxycodone. The maintenance medication was either buprenorphine or the G protein-biased mu opioid receptor agonist TRV130. We then tested prevention of oxycodone seeking and taking during abstinence using a modified context-induced reinstatement procedure, a rat relapse model.
We trained rats to self-administer oxycodone (6 hours/day, 14 days) in context A; infusions were paired with discrete tone-light cues. We then implanted osmotic pumps containing buprenorphine or TRV130 (0, 3, 6, or 9 mg/kg/day) and performed 3 consecutive tests: lever pressing reinforced by oxycodone-associated discrete cues in nondrug context B (extinction responding), context-induced reinstatement of oxycodone seeking in context A, and reacquisition of oxycodone self-administration in context A. We also tested whether TRV130 maintenance would protect against acute oxycodone-induced decreases in nucleus accumbens oxygen levels.
In male rats, buprenorphine and TRV130 decreased extinction responding and reacquisition of oxycodone self-administration but had a weaker (nonsignificant) effect on context-induced reinstatement. In female rats, buprenorphine decreased responding in all 3 tests, while TRV130 decreased only extinction responding. In both sexes, TRV130 prevented acute brain hypoxia induced by moderate doses of oxycodone.
TRV130 decreased oxycodone seeking and taking during abstinence in a partly sex-specific manner and prevented acute oxycodone-induced brain hypoxia. We propose that G protein-biased mu opioid receptor agonists, currently in development as analgesics, should be considered as relapse prevention maintenance treatment for opioid addiction.
阿片类药物（丁丙诺啡、美沙酮）激动剂维持治疗对阿片类药物成瘾有效，但并不能消除所有患者的阿片类药物使用。我们在自行给予处方类阿片类药物羟考酮的大鼠中模拟了维持治疗。维持药物为丁丙诺啡或 G 蛋白偏向性μ阿片受体激动剂 TRV130。然后，我们使用改良的情境诱发复吸程序，即大鼠复吸模型，测试了在禁欲期间预防羟考酮觅药和服用的效果。
我们训练大鼠在情境 A 中自行给予羟考酮（6 小时/天，14 天）；输注与离散的音-光线索配对。然后，我们植入含有丁丙诺啡或 TRV130（0、3、6 或 9mg/kg/天）的渗透泵，并进行了 3 次连续测试：在无药物的情境 B 中，用与羟考酮相关的离散线索强化的压杆按压（消退反应），在情境 A 中诱发羟考酮觅药，以及在情境 A 中重新获得羟考酮自我给药。我们还测试了 TRV130 维持治疗是否能防止急性羟考酮引起的伏隔核氧水平降低。
在雄性大鼠中，丁丙诺啡和 TRV130 降低了消退反应和重新获得羟考酮自我给药，但对情境诱发的复吸影响较弱（无统计学意义）。在雌性大鼠中，丁丙诺啡降低了所有 3 项测试中的反应，而 TRV130 仅降低了消退反应。在两性中，TRV130 均防止了中等剂量羟考酮引起的急性脑缺氧。
TRV130 以部分性别特异性的方式降低了禁欲期间的羟考酮觅药和服用，并防止了急性羟考酮引起的脑缺氧。我们提出，目前作为镇痛药开发的 G 蛋白偏向性μ阿片受体激动剂，应被视为阿片类药物成瘾的复吸预防维持治疗。
